Abstract
BackgroundAbundant experimental data have implicated an important role for insulin-like growth factor (IGF) in protecting neuronal cells from injury, including hypoxia/ischemia (H/I) injury, a major cause of neuron death. While the specific interaction of IGFs with neuronal or glial type 1 IGF receptors (IGF1R) has been shown to be essential to IGF actions during development, the same has not been directly demonstrated following H/I injury. To directly examine the role of neuronal IGF1R following H/I injury, we utilized conditional mutant nes-igf1r-/Wt mice and determined the impact of IGF1R haplodeficiency specifically in nestin-expressing neuronal precursors and their progeny on H/I-induced neuronal damage and apoptosis in hippocampus.ResultsH/I induced significant damage to the cerebral hemisphere and hippocampus ipsilateral to the ligated right common carotid artery both in control and nes-igf1r-/Wt mice at postnatal day 10. Blunting IGF1R expression, however, markedly exacerbated H/I-induced damage and appeared to increase mortality. In the ipsilateral hemisphere and hippocampus, nes-igf1r-/Wt mice had infarct areas double the size of those in controls. The size of the ipsilateral hemisphere and hippocampus in nes-igf1r-/Wt mice were 15% to 17% larger than those in controls, reflecting more severe edema. Consistent with its effects on infarct area, IGF1R haplodeficiency causes a greater decrease in neurons in the ipsilateral hippocampus of nes-igf1r-/Wt mice. The reduction in neurons was largely due to increases in neuronal apoptosis. Judged by pyknotic nuclei, TUNEL and caspase-3 labeling, nes-igf1r-/Wt mice had significantly more apoptotic cells than that in controls after injury. To determine possible mechanisms of IGF1R actions, the mRNA expression of the pro-survival proteins IAP-1 and XIAP was determined. Compared to controls, the abundance of cIAP-1 and XIAP mRNA was markedly suppressed in mice with blunted IGF1R or IGF-I expression, while was increased in the brain of IGF-I overexpressing transgenic mice.ConclusionIGF1R in neuronal cells is critically important for their survival following H/I injury, and IGF-upregulated expression of neuronal cIAP-1 and XIAP likely in part contributes to IGF-IGF1R protection against neuronal apoptosis following H/I injury.
Highlights
Abundant experimental data have implicated an important role for insulin-like growth factor (IGF) in protecting neuronal cells from injury, including hypoxia/ischemia (H/I) injury, a major cause of neuron death
We found that nesigf1r-/Wt mice with blunted IGF1R expression in nestin-expressing neuronal precursors and their progeny exhibit exacerbated H/I-induced injury
We show that a reduction in signaling through IGF1R significantly down-regulates the mRNA expression of cellular inhibitor of apoptosis protein (cIAP)-1 and Xlinked IAP (XIAP), two IAP family proteins that are capable of suppressing cell apoptosis in multiple cell types, including neurons
Summary
Abundant experimental data have implicated an important role for insulin-like growth factor (IGF) in protecting neuronal cells from injury, including hypoxia/ischemia (H/I) injury, a major cause of neuron death. Des-IGF-I, an IGF-I analog lacking the N-terminal three peptides, retains the high affinity of the native peptide for the IGF1R, but has greatly reduced affinity for IGF binding proteins (IGFBPs) It is generally more potent than native IGF-I, because its actions are not inhibited by IGFBPs. Guan et al [17] showed that des-IGF-I was much less effective than native IGF-I in mitigating H/I-induced brain damage, suggesting that IGF-I could exert its effects independent of IGF1R and/or that it requires IGFBPs
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